1. Field of the Invention
The present invention relates to neuropharmacology and in particular to the pharmacological use of uridine in the treatment of those nervous disorders due to a modified dopaminergic balance, such as schizophrenia and Parkinson's disease.
2. Description of the Prior Art
It is already known in the state of the art (reference is made to the European published application number 0178267) that an administration of uridine has a protective effect on certain cerebral hormonal peptides, in particular somatostatin and cholecystokinin, when an insulinic hypoglycemia is induced in rat in an animal pathology pattern.
Cholecystokinin (CCK) is a hormonal peptide having 33 aminoacid residues, which acts in various manners both on the gastro-intestinal tract, and on the central nervous system (CNS) of mammals.
Psychopharmacology, Raven Press, 1987, Chapter 130, pages 1258-1260 describes that at the intestine level CCK produces contraction of the gall bladder, decrease of gastric emptying, and stimulation of pancreatic enzyme secretion. Systemic injection of CCK produces a potent dose-related suppression of feeding in a wide variety of animals, including monkeys. In humans, intravenous infusion of CCK reduces food intake both in obese and lean subjects.
It is also known in the state of the art (Ann. Rev. Pharmacol., 23, 7-9, 1983) that at the CNS level, CCK appears to act through its octapeptide fragment, denominated CCK-8, which appears to be present mainly in cerebral areas, such as cortex, hyppocampus, amigdala and hypothalamus. Particularly in the cortex, CCK appears to be the most widespread hormonal peptide.
Furthermore, it has been known in the state of the art for some years (see Nature 285, 476-478, 1985) that the hormonal peptides present in CNS are almost always associated to classic neurotransmitters (catecholamine, serotonine, gaba, and the like) presumably for modulating their physiologic activity on neurons.
In particular CCK was found almost always associated to dopamine, which is one of the most important catecholamines of CNS.
Dopamine is in fact one of the most important neurotransmitters, and it is known that an altered balance thereof produces serious psychic disorders, such as schizophrenia and psychomotive disorders, such as Parkinson's disease.
The discovery that CCK results to be always associated to dopamine has stimulated a lot of studies on the interactions between CCK and dopamine, on the basis of which the belief has been obtained that CCK acts as neuromodulator with respect to dopamine, in that:
(a) CCK can activate the hyperpolarized dopaminergic neurons;
(b) CCK can increase the activity of dopaminergic neurons, namely the dopamine producing neurons, in the areas in which both CCK and dopamine exist together (dopamine will be hereinafter shortened into DA);
(c) CCK is able to induce a tonic state of inactivation in certain dopaminergic neurons;
(d) it is able to enhance the inhibition of dopaminergic neurons induced by low doses of apomorphine (see Pharmacol., page 116).
As a consequence according to the state of the art, CCK has been considered as a possible drug for treating schizophrenia, in view of its recognized properties of modulating the dopaminergic receptor.
In fact, whereas it is still uncertain whether schizophrenia can be considered a single disease as far as a single etiology and a single optimal treatment are concerned, in the last ten years a considerable therapeutic progress has been made by the development of ever more selective drugs.
The results of the first tests using chlorpromazine had caused to be accepted the evidence that all the neurolectics developed in the past reduced psychosis through a block of the DA receptors. However, this treatment often resulted in acute and chronic side effects, which in humans were manifested by Parkinson type tremors and tardive dyskinesia.
Consequently the strategy was followed of developping new antipsychotic drugs by using the selective antagonism on certain receptor sites of DA. This has been possible in that in the last years more and more information has been obtained concerning the central dopaminergic system, its anatomy, biochemistry and physiology, along with its multiple capability of interaction with other neurotransmitters.
CCK-8 was therefore supposed to be a possible drug of new type for schizophrenia, both in that it is mainly located at the cortex level, and in that it is located together with DA in mesencephalic dopaminergic neurons. As is described in the abovementioned Psychopharmacology, on pages 721-722, as well as 736-737 and 1137-1138, CCK-8 has been tested for its antipsychotic action in schizophrenic subjects by some Japanese students. This initial study referred that CCK-8 was a rather powerful antipsychotic.
Preclinical studies were then undertaken to investigate efficiency and mechanism of action of CCK-8. Whereas these studies are at present under prosecution, confirming a strong action of CCK-8 in schizophrenia, however, the controlled clinical tests successively carried out have been consistantly negative. Not only psychosis, but also other centrally mediated functions, such as visual evoked potential and involuntary movements in the patients failed to change with CCK-8. The peptide also fails to alter the symptoms in severely affected Parkinson's disease patients. On the other hand, in animal models and in vitro experiments, CCK-8 modulates the release of DA from nerve terminals. These central actions occur in rats when CCK is injected directly into the brain or it is placed in contact with the tissues. An explanation of the negative clinical results of CCK-8 in the treatment of schizophrenia is that the peptide fails to enter the brain with systemic administration, as it has been evidenced in tests with monkeys, in that it is not able to cross the blood-brain barrier.
This results in the conclusion that an improvement of psychosis in schizophrenia cannot be obtained by administration of CCK.